PARENT R00 PROJECT SUMMARY Almost half of American adults over 60 years old report being lonely, a condition that can have a major impact on health and mortality risk in later life. Adults with weak social relationships experience a 50% higher mortality rate than more socially integrated adults?an effect on par with that of smoking, obesity, or alcoholism. One explanation for this association is if better social integration increases resilience against stressful experiences, a hypothesis known as ?stress buffering.? Yet despite the importance of social integration for human health, the behavioral and molecular mechanisms that mediate its potential role in stress buffering remain poorly understood, limiting its practical application to improving resilience during aging. The objective of the proposed study is to identify the genomic mechanisms that link social integration to stress sensitivity and inflammation. I hypothesize that low levels of social integration will be associated with dysregulation of the gene regulatory response to acute stress. To test this, I will leverage the advantages of studying rhesus macaques, a well-established animal model for human aging and social behavior. Work performed during the mentored phase of this award has shown that the social environment alters the epigenomic and genomic landscape of immune cells and that these changes may underlie variation in acute stress susceptibility in individuals who have more favorable vs. more adverse social environments. These findings suggest a potential mechanism, epigenomic changes, through which social adversity may accelerate the aging process. Probing how age and social experience interact to alter this mechanism will be the focus of the independent phase of this project. This project will combine studies of free-ranging macaques (Aim 1) with experimental manipulations of the social environment (Aim 2) to yield insight into the relationship between acute stress and gene regulation in a natural environment and a more controlled setting. In both contexts, I will combine genome-wide gene expression, DNA methylation, and chromatin accessibility measurements to characterize the genomic pathways associated with social integration and its relationship with the acute stress response. I will also test whether these relationships are exaggerated for older animals, and whether the presence of a close social partner can enhance resilience to psychosocial stress. At its conclusion, this project will yield a detailed understanding of how social integration impacts gene regulation in pathways that become dysregulated with age and whether social support can buffer against acute stressors at the genomic level. Together, these results will significantly advance our understanding of the mechanisms through which social integrations promotes resilience in the elderly.